The present invention relates to pharmaceutical compositions containing 5-trifluoromethyl-2'-deoxycytidine and a cytidine deaminase inhibitor, and to a method for treating diseases caused by Herpes or Herpes-like virus by administering 5-trifluoromethyl-2'-deoxycytidine and a cytidine deaminase inhibitor.
Diseases caused by Herpes and Herpes-like viruses are particularly widespread in man. Examples of Herpes viruses are Herpes simplex virus (HSV) Types 1 (HSV-1) and 2 (HSV-2) and Herpes varicella-zoster virus (VZV) that causes chicken pox in children and shingles in adults. Other examples of Herpes-like viruses are Epstein-Barr virus, Pseudorabies virus, Cytomegalo virus, Marek's disease virus of chickens, equine abortion virus (EAV) and Lucke-frog virus.
Herpes simplex viruses are strongly implicated in many pathological systems and include ocular (Keratitis), cutaneous (including genital and oral), and systemic disseminated infections. One disease caused by the Herpes simplex virus Type 1 (HSV-1) is a particularly virulent form of encephalitis which, if not treated effectively, is usually fatal. Recurrent and persistent genital infections occur with HSV-2 that are widespread in the population and defy management so that these patients suffer great physical discomfort and psychological distress. HSV-1 causes substantial discomfort to a large segment of the population. There is at this time no known way to manage recurrent infections or to combat this virus in its latent stage.
Varicella-zoster is often the cause of morbidity in immunosuppressed patients such as kidney transplant recipients. Cytomegalo virus causes embryological abnormalities, perinatal neurological disease and great problems in the neonate; like zoster, it is a neurotropic virus.
An extremely active area of the current medical research is the study of virus caused diseases, in particular those induced by Herpes and Herpes-like viruses. An important part of this research is the development of selective antiviral agents for the treatment of these diseases. As will be discussed in more detail below, the major problem with the antiviral agents presently available is their tendency to undergo catabolism in the body and, more importantly, their toxicity towards uninfected cells; that is, their nonselectivity.
The search for effective antiviral agents which exhibit specific antiviral activity against cells infected with Herpes and Herpes-like viruses has met with varying degrees of success. In 1962, Kaufman (IDU Therapy of Herpes Simplex, Arch. Ophthalmol. 67, 583, 1962) investigated the antiviral activity of certain 5-halo-deoxyuridine compounds and found tht 5-iodo-2'-deoxyuridine (IdU) exhibits antiviral activity against HSV infections of the eye. Subsequently, Heidelberger discovered that, while 5-fluorodeoxyuridine exhibits very little antiviral activity, 5-trifluoromethyl-2'-deoxyuridine, or 5-trifluoro thymidine (F.sub.3 dT), does exhibit antiviral activity against infections of the eye. The compound F.sub.3 dT is described and claimed in U.S. Pat. No. 3,201,387. ##STR1##
Although IdU is effective against Herpes Keratitis it is less effective than F.sub.3 dT and is not as effective in systemic infections or in the treatment of Herpes genitalis.
Despite exhibiting antiviral activity, these two compounds (IdU and F.sub.3 dT) suffer from two major disadvantages. The first is that the compounds undergo rapid catabolism in the body which results in significant reduction of antiviral effectiveness of the compound. The second disadvantage is that the compounds exhibit toxicity towards uninfected cells which, in turn, results in the generation of unpleasant and harmful side effects. IdU has been abandoned for the treatment of Herpes encephalitis because of its toxicity and its ineffectiveness, and F.sub.3 dT has not been considered for the treatment of systemic infections. There are some approaches that involve direct intracranial injection of this compound for the treatment of encephalitis; however, the studies are still at the stage of animal models. Furthermore, the approach to treatment appears to be associated with potential hazards for use in humans.
Studies on various 5-substituted analogs of deoxyuridine, including 5-methyl amino-2'-deoxyuridine, 5-thiocyanato-2'-deoxyuridine, 5-ethyl-2'-deoxyuridine, 5-propyl-2'-deoxyuridine, 5-phenyl-2'-deoxyuridine and 5-allyl-2'-deoxyuridine have been reported which indicate that these compounds do exhibit antiviral activity against Herpes simplex in cell culture; however, the success of these compounds will likely remain limited to cell culture studies, in spite of the fact that they are non-toxic in culture, for they are substrates for the catabolic enzymes uridine and thymidine phosphorylase.
Adenine arabinoside has been shown to decrease the incidence of death due to human encephalitis. However, the number of individuals with neurological sequelae was discouraging. That is, the drug decreased the mortality but increased the morbidity. Furthermore, ara-A or ara-AMP is neither effective against recurrent genital Herpes nor does it decrease the incidence of latent virus infection. Phosphonacetic acid is effective in animal systems; however it must be administered in most cases very soon after infection, and is usually ineffective if the onset of treatment is delayed to coincide with realistic intervals for consideration for use in humans.
Other drugs such as ara-T, 4-amino-5-iodo-deoxyuridine and acycloguanine are in various stages of development and are far from being ready for use in clinical studies. Furthermore, in view of the capacity of viruses to mutate to resistance to a drug (as is the case with phosphonacetic acid) it is likely that ultimately viral chemotherapy will involve a combination of drugs that act via different mechanisms.
More recently, attention has turned to the study of deoxycytidine compounds as possible antiviral agents and, in particular, the 5-substituted analogs thereof. Greer et al. (Annals of the New York Academy of Sciences, Volume 255, 359, 1975) have studied the antiviral activity of 5-halo-2'-deoxycytidines, namely 5-bromo-2'-deoxycytidine (BrdC) and 5-iodo-2'-deoxycytidine (IdC). The studies have shown that these 5-halo-2'-deoxycytidine compounds possess a similar antiviral activity against HSV infected cells as that possessed by the corresponding 5-halo-2'-deoxyuridine compounds, but most importantly that the 5-halo-2'-deoxycytidine compounds are substantially less toxic towards uninfected cells than the deoxyuridine compounds. Kurimoto et al. Folia. Ophthalmol. Japan, 20, 49 (1969) have shown that IdC is more effective in the treatment of Herpes Keratitis in humans than IdU.
A drawback of the 5-halo-2'-deoxycytidine compounds is their tendency to undergo deamination in the presence of deaminating enzymes, such as cytidine deaminase. Such enzymes are usually present in the blood and catalyze the deamination of the 5-halo-2'-deoxycytidine compound to the corresponding 5-halo-2'-deoxyuridine compound. As a result of this deamination, uridine compounds are formed which do not display selectivity and which exhibit toxicity towards uninfected cells and generate unpleasant and harmful side effects. Furthermore, deoxyuridine analogs are further degraded to metabolites that do not display antiviral activity.
In order to overcome this problem of deamination, it has been found necessary to employ a deamination inhibitor, and tetrahydrouridine (H.sub.4 U) and 2'-deoxytetrahydrouridine (H.sub.4 dU) have been found particularly suitable for this purpose. These two compounds are described in U.S. Pat. No. 4,017,606 (Hanze et al.). The patent describes the synthesis of H.sub.4 U and H.sub.4 dU starting from a compound whose general formula covers the compound 5-trifluoromethyl-2'-deoxycytidine(F.sub.3 methyl dC) which forms the subject of the present invention. However, there is no specific disclosure of F.sub.3 methyl dC in the Hanze et al. patent and there is no disclosure of any utility of F.sub.3 methyl dC as an antiviral agent.
Studies have been recently reported of the antiviral activity of 5-methyl-2'-deoxycytidine and 5-ethyl-2'-deoxycytidine. Shugar (J. Med. Chem., Vol. 17, No. 3, 296, 1974) discovered that 5-ethyl-2'-deoxycytidine possesses only a low antiviral activity against HSV infected cells and no activity against vaccinia and vesicular stomatitis. Very recent studies by Lin and Prusoff (Abstracts of Papers, 174th ACS Meeting, American Chemical Society, Aug. 28-Sept. 2, 1977) have shown that 5-methyl-2'-deoxycytidine is less effective as an antiviral agent against HSV infected cells than 5-methyl-2'-deoxyuridine.